Candidate: Eric Smith, MD PhD, is an Assistant Attending on the Myeloma Service at Memorial Sloan Kettering Cancer Center, and a post-doc in the lab of his proposed K08 mentor, Renier Brentjens, MD PhD. In the Brentjens lab, Dr. Smith developed optimized fully human chimeric antigen receptor (CAR) vectors for the treatment of multiple myeloma (MM). B cell maturation antigen (BCMA) targeted CAR T cells stemming from his work are under clinical evaluation in four separate clinical trials, including a multi-institution phase I/II registration study. G-protein-coupled receptor C5D (GPRC5D; a novel target he validated for the immunotherapy of MM) targeted CAR T cells he developed are scheduled to enter clinical investigation in 12/2018. While response rates to BCMA targeted CAR T cell therapy are high, many patients go on to relapse. Dr. Smith proposes to study mechanisms of CAR T cell relapse, with a focus on interactions in the MM tumor microenvironment (TME) that may lead to sub-optimal responses, and evaluate novel CAR vectors to enhance CAR T cell efficacy. In the course of carrying out this research, he plans to acquire the technical and intellectual skills and experience required to transition successfully to independent laboratory investigator. Career Development Plan: Dr. Smith has a detailed career development plan based on mentorship, an advisory committee, collaborators, and select course work. Dr. Brentjens, his primary mentor, will continue to provide training and development relating to CAR T cell therapy and T cell biology. His advisory committee has complementary expertise that will enhance his training and development. All advisors have extensive expertise on advanced mouse models of cancer. Dr. Wolchok is an expert on T cell immunology; Dr. Wendel has significant experience with CRISPR; Dr. Abdul-Wahab is a leader in genetics of hematologic malignancies, including gene expression analyses; and Dr. Dhodapkar has spent his career studying the MM microenvironment. Additional informal interactions and formal course work will contribute to Dr. Smith's development in the above areas as well as CyTOF data analysis and biostatistics. Grant writing, presentation, and leadership skills will be enhanced throughout the grant period. These experiences will lead to the establishment of an independent lab group focused on adoptive cellular therapy and an R01 application. Research Plan: In aim 1, Dr. Smith will address target antigen loss mediated relapse by comparing multiple BCMA/GPRC5D dual-targeted CAR T cell strategies in a model of antigen escape to determine an optimal dual-targeting approach. Aim 2, focuses on understanding antigen positive relapse in the setting of the human MM TME through use of the multiply-transgenic humanized MISTRG6 murine model that uniquely supports MM cells and associated bone marrow immune cells, as well as through the study of marrow samples from CAR T cell treated patients. He will assess rational armored CAR approaches that may overcome MM TME immune suppression in order to enhance the durability of response to CAR T cell therapy in advanced MM.